The Nebivolol-hydrochloride salt of a general formula I.

(±)-[(S,R,R,R)+(R,S,S,S)-]-α,α′-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol], (Nebivolol), is a potent and selective β1 adrenergic blocker used for treatment of high blood pressure. Nebivolol has basic properties and may be converted into its addition salts through treatment with suitable acids. Nebivolol is applied in the form of it's racemate and consists of the two enantiomers: d-nebivolol*HCl Ia and l-nebivolol*HCl Ib. The hydrochloric acid addition salt is the marketed product as disclosed in U.S. Pat. No. 4,654,362 A and its counter EP 0145067 A2.

Numerous syntheses for the preparation of nebivolol hydrochloride have been disclosed, for example in U.S. Pat. No. 4,654,362 A (JANSSEN), EP 0334429 A1 (JANSSEN), WO 2004/041805 A1 (EGIS), WO 2006/016376 A1 and WO 2007/083318 A1 (HETERO DRUGS), WO 2006/025070 A2 (TORRENT), WO 2008/010022 A2 (CIMEX), WO 2008/064826 A2 and WO 2008/064827 A2 (ZACH), WO 2009/082913 A1, CN 101463024 A, WO 2010/049455 (ZACH) and WO 2010/089764 A1 (ZACH).
In general, most of the reported processes apply the reaction of two 6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran building blocks formula A
with benzyl amine. Usually, the initially resulting 6-fluoro-3,4-dihydro-2-[[(phenyl)amino]methyl]-2H-1-benzopyran-2-methanol E′
is isolated and purified before final conversion to benzyl protected nebivolol [phenylmethyliminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol.
The patent applications WO 2006/016376 A1, WO 2007/083318 A1 and US 2009/0076288 filed by Hetero Drugs Ltd. disclose the separation of benzyl protected nebivolol by precipitation of the hydrochloride salt. The goal of those patents is the purification of benzyl-nebivolol by fractional crystallization of a crude mixture consisting of several nebivolol diastereomers.
Even if hydrochloride salt intermediates are prepared, all reported processes perform a conversion of the benzyl protected hydrochloride salt and a subsequent deprotection of benzyl protected nebivolol free base in order to get nebivolol free base. The hydrochloride salt of Nebivolol is finally prepared in the last step of the manufacturing process.
In WO 2011/091968 A1 we disclosed a highly stereoselective approach for the synthesis of racemic nebivolol (racemic mixture of d-nebivolol and l-nebivolol) as well as for the production of the individual enantiomers d-nebivolol and l-nebivolol based on enantiomerically pure chloroketones and chloroalcohols, wherein a key step of the method is a stereoselective enzymatic reduction. The hydrochloride salt of Nebivolol may be prepared in the last step of the manufacturing process.
The synthesis is performed according the general scheme 1.

For example, d-nebivolol Fa was prepared by enzymatic reduction of 1-(2S)-(6-fluorochroman-2-yl)-2-chloroethan-1-one Ca and 1-(2R)-(6-fluorochroman-2-yl)-2-chloroethan-1-one Cb to give either the S- or the R-configurated chloroalcohol Ba or Bb. (S)-2-chloro-1-((R)-6-fluoro-3,4-dihydro-2H-chromen-2-yl)ethanol Ba was subjected to amination by treatment with sodium methoxide followed by reaction with benzylamine to give (S)-2-benzylamino-1-((R)-6-fluoro-3,4-dihydro-2H-chromen-2-yl)ethanol Da. This underwent coupling with (R)-2-chloro-1-((R)-6-fluoro-3,4-dihydro-2H-chromen-2-yl)ethanol Bb followed by debenzylation to give d-nebivolol Fa. An analogue pathway applies if Bb was subjected to amination. l-Nebivolol Fb was produced in a similar way. Finally, d- and l-nebivolol (Fa and Fb) were mixed to give racemic nebivolol G which can be converted to the hydrochloride salt.
One of the main issues within this approach is the removal of unwanted stereoisomers of nebivolol built in the individual coupling reactions. This is caused by the fact that the starting chloroketones Ca and Cb are generally prone to epimerisation and traces of the unwanted chloroketone enantiomers can't be completely avoided in the manufacturing process and can reach levels up to 5%. These impurities lead to diastereomeric impurities in Ba-Bd and Da-Dd, and finally in Fa and Fb, too.
In consequence, the formation of unwanted nebivolol stereoisomers may need additional crystallisation steps in the last stages of the synthesis in order to remove these impurities completely to reach a content in the final product <0.1%.
WO 2010/049455 (Zach Systems) formally describes the usage of Benzyl-protected Nebivolol hydrochloride in the transfer hydrogenation (in enantiomerically pure form, see example 1, 2 in WO 2010/049455), but the hydrochloride is converted first to the free base by alkali before running the hydrogenation reaction. The transfer hydrogenation itself is carried out in the presence of formic acid which initially leads to the formation of Nebivolol formate salts. To get the hydrochloride the formate salts have to be converted to the free base first. Only after the debenzylation d-nebivolol and l-nebivolol are mixed to a racemate.
IN 2012MU02522 discloses the debenzylation of d- and l-N-Benzyl-Nebivolol Hydrochloride in presence of ammonium formate, but the resulting nebivolol formate again needs the conversion to the hydrochloride.
Mixing of d- and l-Benzyl-Nebivolol before the final deprotection step has been described in CN 102344431, CA 101463024, WO 2009/082913, EP 2236510, WO 2007/083318, and WO 2006/016376), but in neither case the hydrochloride salt has been used.
All of the before mentioned methods provide nebivolol hydrochloride with a several conversion or purification steps, which comprise naturally a loss of product during the process compared to a method using less conversion or purification steps.
The goal of the present invention is to provide an improved and economical process for preparation of nebivolol hydrochloride salt directly from its protected precursor.